The present invention relates to substituted phenyl compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1xcex2 (IL-1xcex2) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes and mesangial cells.
Certain substituted acetamide compounds are known from EP-A-382 216 having anti-allergic activity.
It would be desirable to make compounds effective as P2X7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X7 receptor may play a role.
In accordance with the present invention, there is therefore provided a compound of general formula 
wherein:
each R1 independently represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom, or a trifluoromethyl, cyano, nitro, C1-C6 alkyl or C1-C6 alkoxy group;
T represents an oxygen atom or, preferably, a group NH;
U represents an oxygen or sulphur atom or a group NH, preferably an oxygen or sulphur atom;
Ar represents a group 
X represents a bond, an oxygen atom or a group CO, CH2, CH2O, O(CH2)m, CH2OCH2, NR5, CH2NR5, NR5CH2, CH2NR5CH2, CONR5, S(O)n or SO2NR5;
m is 1, 2or 3;
n is 0, 1 or 2;
one of R2 and R3 represents a halogen, cyano, nitro, amino, hydroxyl, or a group selected from C1-C6 alkyl optionally substituted by at least one C3-C6 cycloalkyl, C3-C8 cycloalkyl, C1-C6 alkyloxy optionally substituted by at least one C3-C6 cycloalkyl, C3-C8 cycloalkyloxy, S(O)pC1-C6 alkyl or S(O)qC3-C8 cycloalkyl, each of these groups being optionally substituted by one or more fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen atom or a methyl group;
p is 0, 1 or 2;
q is 0, 1 or 2;
R4 represents di(C1-2 alkyl)N(CH2)t where t is 0, 1 or 2 or imidazolyl, or R4 represents a 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, C1-C6 alkyl, acetyl, hydroxy C1-C6 alkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7, xe2x80x94CONR6R7 and pyrimidinyl, or R4 represents a 3- to 8-membered saturated carbocyclic ring system substituted by one or more substituents independently selected from NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7 the ring system being optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl;
r is 1, 2, 3, 4, 5 or 6;
R5 represents a hydrogen atom or a C1-C6 alkyl or C3-C8 cycloalkyl group; and
R6 and R7 each independently represent a hydrogen atom or a C1-C6 alkyl or C3-C8 cycloalkyl group, or R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring, provided that when R3 represents a cyano group, then X is other than a bond;
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched. When one of R2 and R3 represents a C1-C6 alkyl/C1-C6 alkyloxy optionally substituted by at least one C3-C6 cycloalkyl, it should be understood that one or both of the alkyl and cycloalkyl moieties may be optionally substituted by fluorine atoms. A 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms may be a monocyclic or bicyclic ring system. Similarly, a 3- to 8-membered saturated carbocyclic ring system may be a monocyclic or bicyclic ring system. The hydroxyl moiety in a hydroxyalkyl substituent group may be located in any suitable position in the alkyl group. Typically, the hydroxyl moiety will be located on a terminal carbon atom in a straight chain alkyl group. The alkyl groups in a dialkylamino moiety may be the same or different.
Preferably, at least one group R1 is other than a hydrogen atom, especially a halogen atom such as a fluorine or chlorine atom.
Preferably X represents a bond, an oxygen atom or a group CONH, CH2 or O(CH2)m.
One of R2 and R3 represents a halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, nitro, amino, hydroxyl, or a group selected from C1-C6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) optionally substituted by at least one (e.g. 1, 2 or 3) C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C3-C8 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C1-C6 alkyloxy (e.g. methoxy, ethoxy, isopropoxy or tert-butoxy) optionally substituted by at least one(e.g. 1, 2 or 3) C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C3-C8 cycloalkyloxy (e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), S(O)pC1-C6 alkyl (e.g. S(O)pmethyl, -ethyl, -propyl, -butyl, -pentyl or -hexyl) or S(O)qC3-C8 cycloalkyl (e.g. S(O)qcyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl), each of these groups being optionally substituted by one or more (e.g. 1, 2, 3 or 4) fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom or a methyl group.
Preferably, one of R2 or R3 represents a halogen (especially chlorine) atom or a C1-C6 alkyl (especially methyl) group and the other of R2 or R3 represents a hydrogen atom.
In one aspect, R4 may represent a 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl, C1-C6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), acetyl, hydroxyC1-C6 alkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl or hydroxyhexyl), xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7, xe2x80x94CONR6R7 and pyrimidinyl.
The 3- to 9-membered saturated heterocyclic ring system in the group R4 may be a monocyclic ring system such as a pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl or 3-pyrrolidinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl), piperazinyl (e.g. 1-piperazinyl) or homopiperazinyl ring, or a bicyclic ring system such as 
In another aspect, R4 may represent a 3- to 8-membered saturated carbocyclic ring system substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from NR6R7, xe2x80x94(CH2)rNR6R7, and xe2x80x94CONR6R7, the ring system being optionally further substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl).
The 3- to 8-membered saturated carbocyclic ring in the group R4 is preferably a monocyclic ring system such as a cyclopentyl or cyclohexyl ring.
Specific examples of groups R4 include: 
When X represents a bond or a group CO, CH2 or SO2, R4 preferably represents a group: 
When X represents an oxygen or sulphur atom or a group CH2O O(CH2)m, CH2OCH2, NR5, CH2NR5, NR5CH2, CH2NR5CH2, CONR5, SO or SO2NR5, R4 preferably represents a group: 
R5 represents a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or C3-C8, preferably C3-C6, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) group.
R6 and R7 each independently represent a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or C3-C8, preferably C3-C6, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) group, or R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring such as a pyrrolidinyl or piperidinyl ring.
Preferred compounds of the invention include:
2-(3,4-Difluorophenylamino)-N-(2-methyl-5-piperazin-1-ylmethyl-phenyl)-acetamide, trihydrochloride,
2-(3,4-Difluoro-phenylamino)-N-(2-methyl-5-piperazin-1-ylmethyl-phenyl)-thioacetamide,
2-(3,4-Difluoro-phenylamino)-N-(2-methyl-4-piperazin-1-ylmethyl-phenyl)-acetamide, trihydrochloride,
N-(2-Chloro-5-piperazin-1-yl-phenyl)-2-(3,4-difluoro-phenyl amino)-acetamide, trihydrochloride,
(S)-2-(3,4-Difluoro-phenylamino)-N-[2-methyl-4-(2-pyolidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetamide, trihydrochloride,
2-(3-Chloro-4-fluorophenylamino)-N-{2-methyl-5-[3-(4-methylpiperazin-1-yl)-propoxy]phenyl}acetamide,
(+/xe2x88x92)-2-(3-Chloro-4-fluoro-phenylamino)-N-[2-methyl-5-(piperidin4-yloxy)-phenyl]-acetamide, dihydrochloride,
2-(3,4-Difluoro-phenylamino)-N-[2-methyl-4-(piperidin-4-yloxy)-phenyl]-acetamide, dihydrochloride,
(xc2x1)N-[5-(3-Amino-pyrrolidin-1-yl)-2-methyl-phenyl]-2-(3,4-difluoro-phenylamino)-acetamide, trihydrochloride,
2-(3,4-Difluoro-phenylamino)-N-(2-methyl-5-piperazin-1-yl-phenyl)-acetamide, trihydrochloride,
(S)-2-(3,4-Difluoro-phenylamino)-N-(2-methyl-5-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-phenyl)-acetamide,
(S)-2-(3,4-fluoro-phenylamino)-N-[5-(2-hydroxymethyl-pyrrolidin-1-ylmethyl)-2-methyl-phenyl]-acetamide,
2-(3,4-Difluoro-phenylamino)-N-[2-methyl-5-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-phenyl]-acetamide,
2-(3,4-Difluorophenylamino)-N-[2-methyl-3-(piperidin-4-yloxy)phenyl]acetamide trifluoroacetate,
3-[2-(3,4-Difluorophenylamino)acetylamino]-N-(2-dimethylaminoethyl)-2-methylbenzamide,
N-[3-(4-Acetyl-piperazin-1-ylmethyl)-2-methylphenyl]-2-(3,4-difluorophenylamino)acetamide,
2-(3,4-Difluorophenylamino)-N-(3-imidazol-1-ylmethyl-2-methylphenyl)acetamide, and
2-(3,4-Difluorophenylamino)-N-(3-dimethylaminomethyl-2-methylphenyl)acetamide.
The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises:
(i) when U represents an oxygen atom, X represents a CH2 group and R4 represents a 3- to 8-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, C1-C6 alkyl, hydroxyC1-C6 alkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7, xe2x80x94CONR6R7 and pyrimidinyl, reacting a compound of general formula 
wherein one of R10 and R11 represents a hydrogen atom and the other of R10 and R11 represents a group xe2x80x94CH2L1 in which L1 represents a leaving group (e.g. a halogen atom), and T, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Hxe2x80x83xe2x80x83(III)
xe2x80x83in the presence of a base (e.g. diisopropylethylamine), wherein R4xe2x80x2 represents a 3- to 8-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, C1-C6 alkyl, hydroxyC1-C6 alykl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7, xe2x80x94CONR6R7 and pyrimidinyl and wherein R6 and R7 are as defined in formula (I); or
(ii) when U represents an oxygen atom and X represents an oxygen atom or a group O(CH2)m, reacting a compound of general formula 
wherein one of R12 and R13 represents a hydrogen atom and the other of R12 and R13 represents a hydroxyl group, and T, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Yxe2x80x94OHxe2x80x83xe2x80x83(V)
xe2x80x83wherein Y represents a bond or a group (CH2)m and m and R4 are as defined in formula (I), in the presence of 1,1-(azodicarbonyl)dipiperidine and tributylphosphine (under conditions of the Mitsunobu reaction: Tetrahedron Lett. (1993), 34, 1639); or
(iii) when U represents an oxygen atom and X represents a bond, an oxygen atom or a group O(CH2)m, NR5, NR5CH2, CO, CONR5, SO2 or SO2NR5 reacting a compound of general formula 
wherein one of R14 and R15 represents a group xe2x80x94Xxe2x80x2xe2x80x94R4 and the other of R14or R15 represents a hydrogen atom, Xxe2x80x2 represents a bond, an oxygen atom or a group O(CH2)m, NR5, NR5CH2, CO, CONR5, SO2 or SO2NR5, and m, R2, R3, R4 and R5 are as defined in formula (I), with a compound of general formula 
wherein T and R1 are as defined in formula (I), in the presence of a coupling reagent such as isobutylchloroformate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate and a base (e.g. diisopropylarmine); or
(iv) when U represents an oxygen atom and X represents a bond or a group NR5 or NR5CH2, reacting a compound of general formula 
wherein one of R16 or R17 represents a leaving group, L2, such as a halogen atom and the other of R16 or R17 represents a hydrogen atom and T, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Zxe2x80x83xe2x80x83(IX)
xe2x80x83wherein Z represents a hydrogen atom or a group NHR5 or CH2NHR5 and R4 and R5 are as defined in formula (I), optionally in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BINAP) and a base (e.g. cesium carbonate); or
(v) when U represents an oxygen atom and X represents a group CH2O reacting a compound of formula (II) as defined in (i) above with a compound of formula (V) as defined in (ii) above wherein Y represents a bond, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (e.g. silver trifluoromethanesulfonate); or
(vi) when U represents an oxygen atom and X represents a group CH2NR5, reacting a compound of formula (II) as defined in (i) above with a compound of formula (IX) as defined in (iv) above wherein Z represents a group NHR5; or
(vii) when U represents an oxygen atom and X represents a group CH2OCH2, reacting a compound of formula (II) as defined in (i) above with a compound of formula (V) as defined in (ii) above wherein Y represents a group CH2, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (e.g. silver trifluoromethanesulfonate); or
(viii) when U represents an oxygen atom and X represents a group CH2NR5CH2, reacting a compound of formula (II) as defined in (i) above with a compound of formula (IX) as defined in (iv) above wherein Z represents a group CH2NHR5; or
(ix) when U represents an oxygen atom, X represents a group CH2 and R4 represents an unsubstituted 4- to 6-membered saturated heterocyclic ring system containing one nitrogen atom, reacting a compound of formula (II) as defined in (i) above, with a compound of general formula 
wherein s and t independently represent 1 or 2; or
(x) when U represents an oxygen atom and X represents a sulfur atom, reacting a compound of formula (VIII) as defined in (iv) above, with n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x80x94Sxe2x80x94Sxe2x80x94R4xe2x80x83xe2x80x83(XI)
wherein R4 is as defined in formula (I); or
(xi) when U represents an oxygen atom and X represents a CH2 group, reacting a compound of formula (VIII) as defined in (iv) above, with n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x80x94CHOxe2x80x83xe2x80x83(XII)
wherein R4 is as defined in formula (I), followed by a reduction reaction, e.g. with triethylsilane and trifluoroacetic acid or by treatment with methyloxalylchloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile; or
(xii) when U represents an oxygen atom and X represents a bond, reacting a compound of formula (VIII) as defined in (iv) above, with n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4=Oxe2x80x83xe2x80x83(XIII)
wherein R4 is as defined in formula (I), followed by a reduction reaction, e.g. with triethylsilane and trifluoroacetic acid or by treatment with methyloxalylchloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile; or
(xiii) when U represents a sulphur atom, reacting a corresponding compound of formula (I) in which U represents an oxygen atom with a thiolating agent (such as Lawessons"" reagent) at a temperature, for example, in the range from 0xc2x0 to 100xc2x0 C.;
(xiv) when U represents a group NH, reacting a corresponding compound of formula (I) in which U represents a sulphur atom with a suitable alkylating agent (e.g. methyl iodide) followed by reaction with ammonium chloride or ammonia;
(xv) when U represents an oxygen atom and X represents CONR5, reacting a compound of general formula 
wherein one of Rxe2x80x2 or Rxe2x80x3 represents a hydrogen atom and the other of Rxe2x80x2 or Rxe2x80x3 represents a carboxyl group and T, R1, R2 and R3 are as defined in formula (I), with a compound of general formula (XIIIB), R4xe2x80x94NHR5, wherein R4 and R5 are as defined in formula (I); or
(xvi) when U represents an oxygen atom, X represents CH2 and R4 is bonded to X through a nitrogen atom, reacting a compound of general formula 
wherein T, R1, R2 and R3 are as defined in formula (I), with methane sulphonyl chloride followed by reaction with a compound of general formula (XIIID), R4xe2x80x3xe2x80x94H, wherein R4xe2x80x3 is defined as for R4 in formula (I) other than:
di(C1-2 alkyl)N(CH2)t where t is 1 or 2, and
3- to 8-membered saturated carbocyclic ring system substituted by one or more substituents independently selected from NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7, the ring system being optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl;
and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv) or (xvi) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as dichloromethane, tetrahydrofuran, dioxane, xylene or dimethylformamide, at a temperature, e.g. in the range from xe2x88x9278 to 200xc2x0 C., preferably in the range from 0 to 150xc2x0 C.
Compounds of formula (II) in which L1 represents, for example, a chlorine atom may be prepared by reacting a compound of general formula 
wherein one of R18 or R19 represents a hydrogen atom and the other of R18 and R19 represents a protected benzylalcohol group (the protecting group used may, for example, be tertbutyldimethylsilyl) and R2 and R3 are as defined in formula (II), with a compound of formula (VII) as defined above, in the presence of a coupling reagent such as isobutylchloroformate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate and a base (e.g. diisopropylamine), followed by deprotection and reaction with methanesulphonyl chloride in the presence of a base such as diisopropylamine.
Compounds of formula (IV) may be prepared by reacting a compound of general formula 
wherein R2, R3, R12 and R13 are as defined in formula (IV), with a compound of formula (VII) as defined above, in the presence of a coupling reagent such as isobutylchloroformate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate and a base (e.g. diisopropylamine)
Compounds of formula (VI) may conveniently be prepared by reacting a compound of general formula 
wherein L3 represents a leaving group (e.g. a hydroxyl group) and R2, R3, R14 and R15 are as defined in formula (VI), with diphenylphosphoryl azide in the presence of a base such as triethylamine.
Compounds of formula (XVI) in which X represents a bond, an oxygen atom or a group O(CH2)m, NR5 or NR5CH2 can be prepared by reacting a compound of general formula 
wherein R20 represents a hydrogen atom or a C1-C6 alkyl group, one of R21 and R22 represents a leaving group, L4, such as a halogen atom (e.g. bromine or iodine) or a trifluoromethanesulfonate group and the other of R21 or R22 represents a hydrogen atom, and R2 and R3 are as defined in formula (XVI), with a compound of general formula
Hxe2x80x94Xxe2x80x3xe2x80x94R4xe2x80x83xe2x80x83(XVIII)
wherein Xxe2x80x3 represents a bond, an oxygen atom or a group O(CH2)m, NR5 or NR5CH2 and R4 is as defined in formula (I), in the presence of a palladium catalyst (1996 J. Am. Chem. Soc., 7215-6; 1997 J. Am. Chem. Soc., 3395), followed by a hydrolysis reaction (e.g. with sodium hydroxide).
Compounds of formula (XVI) in which X represents CO, CONR5, SO2 or SO2NR5 can be prepared by reacting a compound of general formula 
wherein R23 represents a hydrogen atom or a C1-C6 alkyl group, one of R24 and R25 represents a group COL5 or SO2L5 and the other of R24 or R25 represents a hydrogen atom, L5 represents a leaving group (e.g. a halogen atom) and R2 and R3 are as defined in formula (XVI), with a compound of formula (IX) in which Z represents a hydrogen atom or a group NHR5, in the presence of a base such as diisopropylethylamine and catalytic N,N-dimethylaminopyridine, followed by a hydrolysis reaction (e.g. using sodium hydroxide).
Compounds of formula (VII) may be conveniently prepared by reacting a compound of general formula 
wherein R26 represents a hydroxyl group or a protected nitrogen atom (protected by, for example, a tertbutyloxycarbonyl group) and R1 is as defined in formula (I), with an alkylating agent (e.g. methyl bromoacetate) followed by a saponification reaction.
Compounds of formula (VIII) may be prepared in an analogous manner to compounds of formula (IV) using, instead of the intermediate compound of formula (XV), an intermediate compound of general formula 
R2, R3, R16 and R17 are as defined in formula (VIII).
Compounds of formula (X) can be prepared as described in Syn. Lett. (1998) 379-380.
Compounds of formulae (XIIIA) and (XIIIC) may be prepared by processes analogous to those already described.
Compounds of formulae (III), (V), (IX), (XI), (XII), (XIII), (XIIIB), (XIIID), (XIV), (XV), (XVII), (XVIII), (XIX), (XX) and, (XXI) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, compounds of formula (I) in which one of R2 and R3 represents a nitro group can be converted to compounds of formula (I) in which one of R2 and R3 represents an amino group by reduction using iron powder and ammonium chloride in ethanol/water under reflux conditions. The latter compounds can in turn be converted into compounds of formula (I) in which one of R2 and R3 represents a halogen atom, e.g. chlorine, by diazotization (e.g. with sodium nitrite) and reaction with copper chloride. Compounds of formula (I) in which R6 or R7 represents a hydrogen atom can be converted to compounds of formula (I) in which R6 or R7 represents a C1-C6 alkyl, C3-C8 cycloalkyl or a 3- to 8-membered saturated heterocyclic ring by standard chemical procedures.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve at a certain stage the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of the present invention are advantageous in that they possess pharmacological activity. They are therefore indicated as pharmaceuticals for use in the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn""s disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer""s disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term xe2x80x9ctherapyxe2x80x9d also includes xe2x80x9cprophylaxisxe2x80x9d unless there are specific indications to the contrary. The terms xe2x80x9ctherapeuticxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d should be construed accordingly.
The invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
The invention also provides a method of treating an obstructive airways disease (e.g. asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (I)/salt/solvate (active ingredient) may be in the range from 0.001 mg/kg to 30 mg/kg.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w, more preferably from 30 to 99.90% w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.